Molecular Effects and Functions of the Mediator Complex Specialization During Cell Differentiation

Composition of the Mediator Complex (From Yin et al, Development 2014)
Cellular differentiation is controlled by execution of cell-specific gene expression programs that depend on a plethora of specific transcription factors (TF). TF modulate the activity of a 4.3 MDa complex (Pre-Initiation Complex, PIC) comprising Pol II,  TAFs and the Mediator. While PIC composition has long been considered to be invariant, alternative members have been identified playing pivotal roles in cell differentiation. We recently identified a normal human dermal fibroblast specific mediator subunit essential to maintain skin fibroblasts identity controlling the fibroblast to myofibroblast differentiation process occurring during wound healing. Our preliminary results are consistent with a model by which mediator cell-specific subunits play a major role maintaining a pre-committed cellular state from undergoing differentiation.

We are currently investigating the role of tissue specific mediator subunits in various cellular differentiation systems.

We currently focus our work on 3 main points :

  1. Dicepher the cellular and molecular effects of the specialization of the Mediator complex during cellular differentiation and particularly during fibroblast to myofibroblast differentiation and upon hESC to IPS reprogramming.
  2. Study the regulation of nuclear organization during cell fate determination. Applying biophysical single molecules approaches we measure how chromatin gets reorganized during differentiation and the role played by the mediator.
  3. Track changes in the mediator complex in pluripotent and differentiated cell types. The existence of several Mediator Paralogs in mammalian genomes probably means that our observation will not be restricted to dermal fibroblasts.

Claire Dugast-Darzacq